Perineal Squamous Cell Carcinoma Arising in an Epidermal Cyst.

A 90-year-old Japanese woman who had been aware of a subcutaneous mass on the right perineal region for 5 years was referred to our hospital for further examination and treatment because of the rapid growth of the mass and bleeding that began 3 months earlier. A biopsy of the mass revealed a diagnosis of well-differentiated squamous cell carcinoma. On preoperative examination, the tumor was 90×40 mm in size and was suspected to have partially invaded the levator ani muscle and external sphincter. Since a preoperative cardiac evaluation indicated severe aortic stenosis, we performed transcatheter aortic valve implantation. A radical resection was then performed with general anesthesia. The skin and subcutaneous tissue defects were reconstructed with a posterior gluteal-thigh propeller flap, and a sigmoid colostomy was created. The patient had a good postoperative course and was transferred to a rehabilitation facility 28 days after the surgery. Epidermal cysts are a common benign tumor, and clinicians should keep in mind that these cysts can become malignant.

Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I.

Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.

Intraoperative local instillation anesthesia using injection technique from J-VACTM drain for postoperative pain relief in male-type chest wall contouring surgery.

For postoperative acute pain during mastectomy, a few studies have reported the usefulness of an intraoperative local anesthesia instillation technique in which analgesics are injected through a drain placed under the skin, intraoperatively. This study presented a novel administration method, and the efficacy of local instillation anesthesia in male-type chest wall contouring surgery was assessed. Fifty-four patients underwent chest wall contouring surgery under general anesthesia. The 27 patients in each of the study and control groups, with our instillation technique and without the technique were compared, in terms of the maximum numerical rating scale (NRS) score within 24 h after surgery, the postoperative analgesic use frequency, and dosage until 6 d. The analgesic used was a mixture of 5 ml 1% lidocaine hydrochloride, epinephrine (0.05 mg), 10 ml 0.75% bupivacaine, and 10 ml saline. Thereon, 25 ml analgesia was administered from the left and right drain (15-Fr J-VACTM) and infiltrated for 15 min. Both NRS scores of postanesthesia care unit (PACU) discharge and the maximum NRS score within 24 h after PACU discharge were significantly lower in the study group than in the control group (p < 0.001, p = 0.048). The frequency of analgesics administered within 24 h after surgery was significantly lower in the study group than in the control group (p = 0.025). Our anesthesia instillation method for chest wall contouring surgery was effective in relieving acute pain occurring within 24 h after surgery and can be a useful analgesic administration method.

Smoking Status and Risk Awareness of Heated Tobacco Product Use among General Dental Practitioners Belonging to the Aichi Dental Association, Japan.

The awareness of healthcare practitioners concerning heated tobacco product (HTP) use risks has been evaluated; however, few studies have investigated general dental practitioners' awareness regarding HTP-use risks. In this cross-sectional study, we investigated dentists' awareness of the risks of smoking, particularly HTP use. A self-administered questionnaire, including eight questions on conventional cigarette and HTP smoking/using status and both knowledge and awareness of HTP-use risks, was posted to 3883 dentists belonging to the Aichi Dental Association, Japan, in August 2019. Statistical analysis was performed using the Statistical Package for Social Sciences; statistical significance was set at p < 0.05. We analyzed the data of 1317 dentists (participation rate, 41.6%). The study group included cigarette smokers (11.5%) and HTP users (8.5%), among whom 41.1% were dual users. HTP users were more likely than never smokers/users to correctly perceive HTP-use risks (p < 0.05). This study indicates that in Japan, the proportion of HTP users is higher than that of the general population. It is important to educate not only smokers/users but also never smokers/users on the risks of smoking and using HTPs. Smoking cessation, including ceasing HTP use, and aiming to quit smoking and HTP use among dentists would contribute to appropriate smoking cessation among patients.

Genital Feminizing Surgery without Vaginoplasty as a Safe, Aesthetic, and Cost-Effective Option for Gender-Affirming Surgery for Transwomen.

Gender affirming surgery (GAS) has important impacts for people with gender incongruence (GI), both physically and socially. As the societal acceptance of gender diversity spreads, the number of individuals with GI who wish to be identified as the gender of their choice is increasing. Indeed, many elderly people who have lived a long time with GI now wish to undergo GAS, but face greater surgical risks due to greater burdens of underlying medical conditions. Generally, vaginoplasty is performed for transwomen; however, this surgery is time-consuming and involves heavy bleeding, and thus, should be avoided in elderly people. A less invasive technique is needed. In this article, we describe a new, less invasive genital feminizing surgical technique for transwomen with reports from two clinical cases. We present this novel technique as a safe, aesthetic, and cost-effective option for gender-affirming surgery for transwomen.

Effects of glucokinase activator, DS-7309, on embryo-fetal developmental toxicity in rats and rabbits.

The toxicological effects of DS-7309, a glucokinase activator, on pregnancy and embryo-fetal development in rats and rabbits and maternal blood glucose levels were examined. DS-7309 was administered at 3, 10, or 100 mg/kg to rats from Days 7-17 of pregnancy or at 10, 30, or 100 mg/kg to rabbits from Days 6-18 of pregnancy. In rats, maternal hypoglycemia (approximately 50 mg/dL) was seen at 3 and 10 mg/kg, but it recovered 7 h after dosing, leading to no toxic changes. In contrast, continuous severe maternal hypoglycemia (approximately 40 mg/dL, ≥7 h), fetal eye anomalies, and decreased fetal body weight were noted at 100 mg/kg. In rabbits, no fetal anomalies were seen at 10 and 30 mg/kg where maternal blood glucose level dropped to approximately 60-90 mg/dL, but recovered by 7 h after dosing at the latest. In contrast, at 100 mg/kg, severe hypoglycemia (around 60 mg/dL) was maintained and did not recover until 24 h after dosing; it resulted in decreased fetal viability and increased fetal skeleton anomalies. These findings indicate that DS-7309 could lead to embryo-fetal toxicity in rats and rabbits, with such toxicity considered to be related to continuous severe maternal hypoglycemia.

Pectoralis Major and Serratus Anterior Muscle Flap for Diaphragmatic Reconstruction.

The reconstruction of diaphragmatic defects after chondrosarcoma resection is challenging. In diaphragmatic reconstruction with chest wall defects, strong chest wall reconstruction and diaphragmatic flexibility are important to avoid interference with respiration. The artificial material, Gore-Tex (W. L. Gore & Associates), is used as the first choice, but it has drawbacks related to infection, exposure, and durability. As an alternative method using artificial material, we present our alternative technique for diaphragmatic reconstruction using a reversed-combined pectoralis major and serratus anterior muscle flap.

Rituximab and mepolizumab combination therapy for glucocorticoid-resistant myocarditis related to eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA), which belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, is characterised by eosinophil-rich granulomatous inflammation and small- to medium-sized vessel vasculitis associated with bronchial asthma and eosinophilia. It sometimes causes severe organ damage, of which myocardial damage is one of the most important for determining the prognosis. A case of EGPA-associated myocarditis that was refractory to glucocorticoid therapy and responded successfully to rituximab (RTX) and mepolizumab (MPZ) combination therapy is presented. A 46-year-old woman was diagnosed with EGPA-associated myocarditis due to pre-existing asthma, eosinophilia, mononeuritis multiplex, and eosinophilic myocarditis by myocardial biopsy. Transthoracic echocardiography showed thickening of the cardiac wall, pericardial effusion, and left ventricular hypokinesis. Although the myocarditis was refractory to methylprednisolone pulse therapy followed by oral high-dose prednisolone, the disease activity reached remission with the successful tapering of glucocorticoid after initiation of the RTX and MPZ combination therapy. Combination therapy with RTX and MPZ can be a good treatment option for EGPA-associated myocarditis for which it is difficult to give intravenous cyclophosphamide due to cardiac dysfunction.

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate.

Predicting human disproportionate metabolites is difficult, especially when drugs undergo species-specific metabolism mediated by cytochrome P450s (P450s) and/or non-P450 enzymes. This study assessed human metabolites of DS-1971a, a potent Nav1.7-selective blocker, by performing human mass balance studies and characterizing DS-1971a metabolites, in accordance with the Metabolites in Safety Testing guidance. In addition, we investigated the mechanism by which the major human disproportionate metabolite (M1) was formed. After oral administration of radiolabeled DS-1971a, the major metabolites in human plasma were P450-mediated monoxidized metabolites M1 and M2 with area under the curve ratios of 27% and 10% of total drug-related exposure, respectively; the minor metabolites were dioxidized metabolites produced by aldehyde oxidase and P450s. By comparing exposure levels of M1 and M2 between humans and safety assessment animals, M1 but not M2 was found to be a human disproportionate metabolite, requiring further characterization under the Metabolites in Safety Testing guidance. Incubation studies with human liver microsomes indicated that CYP2C8 was responsible for the formation of M1. Docking simulation indicated that, in the formation of M1 and M2, there would be hydrogen bonding and/or electrostatic interactions between the pyrimidine and sulfonamide moieties of DS-1971a and amino acid residues Ser100, Ile102, Ile106, Thr107, and Asn217 in CYP2C8, and that the cyclohexane ring of DS-1971a would be located near the heme iron of CYP2C8. These results clearly indicate that M1 is the predominant metabolite in humans and a human disproportionate metabolite due to species-specific differences in metabolism. SIGNIFICANCE STATEMENT: This report is the first to show a human disproportionate metabolite generated by CYP2C8-mediated primary metabolism. We clearly demonstrate that DS-1971a, a mixed aldehyde oxidase and cytochrome P450 substrate, was predominantly metabolized by CYP2C8 to form M1, a human disproportionate metabolite. Species differences in the formation of M1 highlight the regio- and stereoselective metabolism by CYP2C8, and the proposed interaction between DS-1971a and CYP2C8 provides new knowledge of CYP2C8-mediated metabolism of cyclohexane-containing substrates.

The COVID-19 Pandemic and Families in Japan.

This paper, which is authored by members of the Japanese Association of Family Therapy (JAFT), describes the COVID-19 pandemic in Japan from a family systems perspective. The authors are active members of JAFT and include current and past presidents and officers. We describe the course of the pandemic and the ways in which government policies to mitigate the pandemic have affected Japanese families. Challenges that affect Japanese families include the inability to participate in family and social rituals, prescribed gender roles that specifically affect women, high suicide rates, and prejudice against those who are at risk of spreading the infection. The need to shelter in place has also forced family homes to function as a workplace for parents, classrooms for children, and day care services for frail elders, which has resulted in psychological distress among individuals and conflicts among families. We discuss ways that therapists have worked with Japanese families using online therapy.

MHC class I transactivator NLRC5 in host immunity, cancer and beyond.

The presentation of antigenic peptides by major histocompatibility complex (MHC) class I and class II molecules is crucial for activation of the adaptive immune system. The nucleotide-binding domain and leucine-rich repeat receptor family members CIITA and NLRC5 function as the major transcriptional activators of MHC class II and class I gene expression, respectively. Since the identification of NLRC5 as the master regulator of MHC class I and class-I-related genes, there have been major advances in understanding the function of NLRC5 in infectious diseases and cancer. Here, we discuss the biological significance and mechanism of NLRC5-dependent MHC class I expression.

Long-Term Effect of Honeycomb ß-Tricalcium Phosphate on Zygomatic Bone Regeneration in Rats.

In recent years, artificial bones with high biocompatibility have been developed for hard tissue reconstruction. However, current bone replacement methods are inadequate for large defects, causing infection, exposure, and damage. We have developed a new honeycomb ß-tricalcium phosphate (TCP) material, which achieved good bone regeneration after implantation in a rat complete zygomatic bone defect. In this study, we further investigated the ability of honeycomb ß- TCP for remodeling after bone regeneration as a long-term result. Bone morphogenic protein (BMP)-2-free honeycomb ß-TCP (TCP group) and honeycomb ß-TCP with BMP-2 (BMP group) were implanted in the zygomatic bone of rats. Micro-computed tomography was performed to track the zygomatic bone morphology, and specimens were histologically examined for osteogenesis and remodeling. In the TCP group, no bone formation was observed at 1 month, but it was observed at 6 months. Bone formation was observed in the BMP group at 1 month, and ß-TCP absorption reproducing the zygomatic bone morphology was observed at 6 months. This honeycomb ß-TCP with BMP-2 may provide appropriate remodeling that reproduces good bone formation in the early stage and good morphology in the long term, offering an alternative bone reconstruction material to vascularized bone grafts.

Effect of Honeycomb ß-TCP Geometrical Structure on Bone Tissue Regeneration in Skull Defect.

The effect of the geometric structure of artificial biomaterials on skull regeneration remains unclear. In a previous study, we succeeded in developing honeycomb ß-tricalcium phosphate (ß-TCP), which has through-and-through holes and is able to provide the optimum bone microenvironment for bone tissue regeneration. We demonstrated that ß-TCP with 300-µm hole diameters induced vigorous bone formation. In the present study, we investigated how differences in hole directions of honeycomb ß-TCP (horizontal or vertical holes) influence bone tissue regeneration in skull defects. Honeycomb ß-TCP with vertical and horizontal holes was loaded with BMP-2 using Matrigel and Collagen gel as carriers, and transplanted into skull bone defect model rats. The results showed that in each four groups (Collagen alone group, Matrigel alone group, Collagen + BMP group and Matrigel + BMP-2), vigorous bone formation was observed on the vertical ß-TCP compared with horizontal ß-TCP. The osteogenic area was larger in the Matrigel groups (with and without BMP-2) than in the Collagen group (with and without BMP-2) in both vertical ß-TCP and horizontal ß-TCP. However, when BMP-2 was added, the bone formation area was not significantly different between the Collagen group and the Matrigel group in the vertical ß-TCP. Histological finding showed that, in vertical honeycomb ß-TCP, new bone formation extended to the upper part of the holes and was observed from the dura side to the periosteum side as added to the inner walls of the holes. Therefore, we can control efficient bone formation by creating a bone microenvironment provided by vertical honeycomb ß-TCP. Vertical honeycomb ß-TCP has the potential to be an excellent biomaterial for bone tissue regeneration in skull defects and is expected to have clinical applications.

Dynamic localization of αB-crystallin at the microtubule cytoskeleton network in beating heart cells.

αB-crystallin is highly expressed in the heart and slow skeletal muscle; however, the roles of αB-crystallin in the muscle are obscure. Previously, we showed that αB-crystallin localizes at the sarcomere Z-bands, corresponding to the focal adhesions of cultured cells. In myoblast cells, αB-crystallin completely colocalizes with microtubules and maintains cell shape and adhesion. In this study, we show that in beating cardiomyocytes α-tubulin and αB-crystallin colocalize at the I- and Z-bands of the myocardium, where it may function as a molecular chaperone for tubulin/microtubules. Fluorescence recovery after photobleaching (FRAP) analysis revealed that the striated patterns of GFP-αB-crystallin fluorescence recovered quickly at 37°C. FRAP mobility assay also showed αB-crystallin to be associated with nocodazole-treated free tubulin dimers but not with taxol-treated microtubules. The interaction of αB-crystallin and free tubulin was further confirmed by immunoprecipitation and microtubule sedimentation assay in the presence of 1-100 µM calcium, which destabilizes microtubules. Förster resonance energy transfer analysis showed that αB-crystallin and tubulin were at 1-10 nm apart from each other in the presence of colchicine. These results suggested that αB-crystallin may play an essential role in microtubule dynamics by maintaining free tubulin in striated muscles, such as the soleus or cardiac muscles.

Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus.

OBJECTIVE: This study aimed to explore the risk factors for 'severe' neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). METHODS: This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan-Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. RESULTS: The median follow-up period was 7.9 years (interquartile range (IQR) 4.6-12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9-6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p < 0.001) emerged as independent risk factors for developing severe NP flare. CONCLUSION: The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.

Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor.

A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.

The Novel Eryngii Method of Nipple Reduction for Female-to-Male Transsexuals.

Mastectomy is usually the first and most important surgical procedure in female-to-male (FTM) individuals with gender identity disorder. Nipple reduction is also important in the process of reconstructing the chest wall for a more male appearance. If the nipples remain large after a mastectomy, the results may be disappointing to many FTM transsexuals. Nipple reduction enables these individuals to go to the beach or Japanese public baths, where they may go topless in public. We therefore consider that nipple reduction is indicated for all FTM transsexuals who desire it. There are a variety of methods for the reduction of enlarged nipples for women or non-FTM patients, but only a few reports have described the process used to create masculine-appearing nipples for FTM transsexuals. We developed a novel technique called the Eryngii method for creating male-like nipples using a 4-mm diameter dermal punch knife. The name of the method refers to the Eryngii king trumpet mushroom, which the nipple resembles after the surgical process. The main strength of this method is that it permits the creation of ideal nipples without difficulty. Here we introduce the technique and discuss our history of surgical methods for nipple reduction, including improvements and elaborations.

Effects of single ingestion of rice cracker and cooked rice with high resistant starch on postprandial glucose and insulin responses in healthy adults: two randomized, single-blind, cross-over trials.

Rice with double mutation of starch synthase IIIa and branching enzyme IIb (ss3a/be2b) has much higher amounts of apparent amylose and resistant starch (RS) than usual varieties. In this study, we conducted two randomized, single-blind, crossover trials to investigate the effect of single ingestion of two processed foods composed of ss3a/be2b mutant rice on postprandial blood glucose and insulin response in healthy adults, compared to those of usual cultivar. In trial 1, of ingestion of rice crackers, the incremental area under the curves of glucose (IAUCglc) and insulin (IAUCins) in RS group was significantly lower than in the control group. In trial 2, of the ingestion of cooked rice, IAUCglc in the RS group was significantly lower than in the control group. These results showed that the ss3a/be2b-mutant rice cracker and cooked rice having high RS can attenuate postprandial blood glucose and insulin response.

Risk Factors for Postoperative Hematoma after Chest Wall Contouring for Female-to-Male Transsexuals: A Clinical Study.

Gender dysphoria is a condition in which a discrepancy between biological sex and gender identity causes distress. Many female-to-male transsexuals (FTMTS) are uncomfortable with female breasts. Chest wall contouring surgery is effective for obtaining a male-type chest, reducing mental stress, and increasing sexual satisfaction in such cases. At the Okayama University Hospital Gender Center, we have obtained positive results using an algorithm to determine the most appropriate surgical method for chest wall contouring in FTMTS patients. However, serious complications requiring reoperation, such as hematoma, may still occur. Postoperative hematomas were found in 15 (4.18%) of 358 FTMTS patients who underwent chest contouring surgery at our hospital between 2006 and 2018. Postoperative hematoma was examined retrospectively. The median time to the onset of hematoma was 7 (6-12) h after the initial surgery. The main blood vessels causing bleeding were those in the head-side skin flap region where visual confirmation was difficult and the perforator vessels from the pectoralis major muscle. Intraoperative bleeding and the operation time had a significant impact on the onset of postoperative hematoma. This is the first retrospective study that investigated the blood vessels and other factors contributing to postoperative hematoma development after chest wall contouring.